I. Field of the Invention
The present invention concerns transdermal delivery of therapeutic agents by use of an applied electromotive force, commonly known as iontophoresis. The system is contained preferably in a rather small skin worn patch which contains electrodes and a therapeutic agent. When applied to the skin, the system completes a circuit and spontaneously initiates the flow of a galvanic current. More particularly, the invention is directed to a capacity-related power source/dosage characterization technique for iontophoresis. The power sources/dosage control systems are based on combinations of a plurality of galvanic couple power sources selected from manufactured lots or batches of such power sources or source components of tested capacity so that each system capacity can also be designated on labels. The system is self contained and the delivery rate may be variable or adjustable.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908, and has since found wide spread acceptance and commercial use in the delivery of ionically charged therapeutic compounds such as pilocarpine, dexamethasone, and lidocaine. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode, while ions bearing a negative charge are driven across the skin at the site of an electrolytic electrical system cathode.
With iontophoretic devices, the application time and level of current flow (usually reported in units of milliamp minutes) between the anode and cathode is directly correlated to the amount of drug delivered. The efficiency of drug delivery in an iontophoretic system can be measured by the proportion of current carried by the drug molecule, relative to the current carried by competing non-medication ions.
Iontophoresis devices have conventionally comprised two electrodes attached to a patient, each connected via a wire to a microprocessor controlled electrical instrument. Medication is placed under one or both of the electrodes, for delivery into the body as the instrument is activated. The instrument is designed to regulate current flow and application time. Examples of such instruments are described in U.S. Pat. Nos. 5,254,081, and 5,431,625. Power for these devices is usually provided by DC batteries, which when providing power for the microprocessor controlled circuitry allow application of a voltage to the electrodes to create a regulated current flow. The automated control of current flow and time (milliamp-minutes) is of great advantage, in order to prevent excessive dosages of therapeutic agents from being delivered. However, these battery powered microprocessor systems are disadvantaged by the fact that patients are ‘attached by wire’ to an instrument, which limits patient mobility and ability to conduct normal daily activities. A typical application period is approximately 20 minutes to 2 hours, which consumes instrument, caregiver, and patient time.
A significant advantage of a microprocessor controlled iontophoretic system is an ability to adjust electrical current as a function of time, while the system is being used. For example, to administer medication quickly into systemic circulation, an initial high flow rate is desired. However, adjustment to a lower flow rate may be desired afterward for optimal maintenance of a particular plasma medication level.
More recently, wearable iontophoretic systems have been developed in which the electrical circuitry and power supplied are integrated into a single patch. These systems are advantageous in that they do not require external wires, and they are much smaller in size. Examples of such systems can be found in U.S. Pat. Nos. 5,358,483; 5,458,569; 5,466,217; 5,605,536; and 5,651,768. However, these systems also have drawbacks. They are relatively inflexible and expensive, owing to the requirements of multiple electronic components, battery power supplies and electrical interconnects.
Power to drive iontophoretic current flow can also be supplied by galvanic means, which utilizes dissimilar anode and cathode materials to produce a spontaneous current flow when they are contacted with the body. These systems hold advantage, in that separate electrical circuitry and battery sources are not required. An iontophoretic device, not of the transdermal type, but one which utilizes galvanic means is described in U.S. Pat. No. 5,322,520, which describes an implanted device designed to deliver oligodynamic metal ions from its surface, in order to kill bacteria on or near it.
Devices suggesting galvanic power as a means to transdermally deliver medication are described in U.S. Pat. Nos. 5,162,042, and 5,405,317. These devices are disadvantaged by the fact that the amount of medication delivered is not automatically regulated, and they require a timely removal of the device from the body to prevent a potentially toxic over- dosage of medication.
In a co-pending application PCT/US99/18861, designating the U.S., claiming priority based on U.S. provisional application No. 60/098,652, assigned to the same Assignee as the present application, an iontophoresis patch system is described which uses galvanic power and provides a known dosage capacity. Thus, this system can be designed to automatically shut off after a specified dosage, and the risk of overdosage is eliminated. That co-pending application is deemed incorporated herein by reference for any purpose.
Horstmann, in U.S. Pat. No. 5,685,837, describes a transdermal therapeutic system which uses series mounted sheet-like galvanic elements as a power source. That device has an ability to either create a constant intensity of current using a high internal resistance element, or create a gradual decreasing current intensity using a low internal resistance element. The low internal resistance, and a decreasing current flow, is caused by a build up of ions into an electrolyte layer of the galvanic element.
While it appears advantageous, there are certain practical disadvantages to the Horstmann system. To achieve a decreasing current, a very thin electrolyte layer required. The thin layer is susceptible to mechanical failure during production or use. Also, rather than the gradual decreasing current of the Horstmann system, a steady high rate of current which then rapidly falls is optimal, so that a known charge dosage can be administered in minimal time. The actual charge dosage administered using the Horstmann device is not accurately known, since a nernstian decline in voltage is in a non-linear diminishing rate, and thus the system will not fall to zero current during practical time scales.
One restriction of all galvanic systems is a limited supply of user-friendly materials which can be practically used. Many materials may be toxic themselves, and/or they may be difficult to work with in the manufacturing process. A significant problem lies with materials that are reactive with water, and therefore can alter the pH of the medication solution during use. pH changes can harm skin, or cause adverse reaction with medication. For example, we have found zinc (E0=−0.763) to be an excellent galvanic material, but magnesium (E0=−2.37) causes a pH change in iontophoretic medication chambers. Silver chloride (E0=+0.222) does not affect pH of a medication chamber, but manganese dioxide (E0=+1.23) does. Consequently, the voltages obtainable in galvanically powered systems are limited by material stability or compatibility. Of course, various other species may have application as oxidizable or reducible species under different circumstances.
Another restriction or limitation of galvanically powered systems is an inability to increase or decrease voltage (and medication delivery) during use. The voltage is fixed by the galvanic half reactions used, and cannot be altered in process. This is a significant disadvantage in circumstances where increasing rate of delivery, such as to administer a bolus of medication, is desired. Accordingly, it would present a great advantage were increased potential available in such a device.
At a given potential, the rate that medications are introduced is a function of the level of current while the total quantity of medication delivered is a function of both current levels and the time, i.e., the amount of total charge transferred. Because of this relation, the quantity of medication introduced by iontophoresis is often referred to in units of mA-minutes of dosage. Thus, for example, an equivalent 40 mA-minute dosage can be delivered at different rates; 0.1 mA for 400 minutes, 1 mA for 40 minutes, 10 mA for 4 minutes, etc. Labeling, of course, can also be in units of charge (coulombs in addition to mA-minutes), equivalent amount of drug (mass, moles), time (hours), amount of electrode material (mass, moles), or other units that relate to total charge capacity of the galvanic couple power source or other battery that gets delivered.
Control of the dosage delivered by iontophoresis is usually accomplished by means of electrical circuitry in the form of electrical components mounted on the circuit layer. Electrical components can be utilized to regulate the level, waveform, timing and other aspects of the electrical current and the system usually also includes a microprocessor adapted to control the current over time. These electrical circuits are well known and are described, for example, in U.S. Pat. No. 5,533,971.
It is well known in manufacturing piece parts that costs are reduced by production in high volume, typically large batch (or lot) quantities. However, it has been discovered that mass production of iontophoretic power supplies to deliver a fixed, pre-determined charge or dosage within close tolerances is difficult to accomplish. In producing large batch quantities, there inevitably exists variability associated with the manufacturing process. Thus, for example, the actual capacity of power supplies produced and so the associated dosage produced in a manufacturing lot often deviates somewhat from the capacity intended (or “target”) dosages. This is not totally unexpected inasmuch as iontophoretic devices of the class are generally designed to optimally deliver a fixed and known charge in a range between about 0.06 and 60 coulombs, which corresponds to between 0.00000062 and 0.00062 gram equivalent weights of oxidizable or reducible species in limiting supply. Clearly, consistency at these low amounts is a challenge.
Additionally, it has been discovered that drift can occur during processing to cause a segment of a lot to deviate from the rest. For example, in building a sequence of parts which constitute a manufacturing lot, nominally between 1,000 and 1,000,000 parts, a first portion of the lot may deviate from a middle or end portion. Even when several devices are prepared in a single manufacturing step, deviations can occur between groupings.
III. Advantages of the Invention
The invention provides galvanically powered iontophoretic devices and methods of making same in which the devices have a power source/dosage control system of reliable capacity which can be labeled and which, by combining components in a desired fashion, can provide any desired time-voltage profile (and consequently customize the rate profile of medication delivery). The devices of the present invention eliminate the need for any microprocessor or human intervention to administer the indicated dosage.
The present invention further provides a solution to overcome the idiosynchroses of manufacture in each lot or batch of galvanic couple power sources or source components by providing a special lot testing technique which characterizes the capacity of the power sources or source components and, in turn, enables dosage capacity to be predicted with a much greater degree of accuracy. This enables the dosage to be designated or labeled on a corresponding device and further enables the power source to, in addition to providing the sole source of power, provide the only dosage control for the iontophoresis system into which it is connected.
An advantage is to provide such a device capable of maintaining voltage at a stable level for a determined known charge dosage, afterwards having an automated ability to adjust the voltage downward or upward to at least a second known voltage and determined charge dosage in rapid fashion, without a microprocessor or other outside control.
A further advantage is the provision of a multi-couple galvanic power system which can be adjusted to higher voltage during use, in order to administer a bolus of medication.
Another advantage resides in a multi-couple, time-variable galvanic power system employing several serially connected galvanic sources of different coulombic capacities in conjunction with parallel or serial connected resistor devices.
Materials used are not reactive in contact with water, w and are stable when used in a manufacturing process.
Other objects and advantages will occur to those skilled in the art upon familiarization with this specification, drawings and appended claims.